This invention relates generally to an efficient process for the preparation of a benzisoxazolyl-pyrazole. Benzisoxazolyl-pyrazoles are useful as factor Xa inhibitors.
Factor Xa inhibitors like those of Formula Ia shown below: 
WO98/57951 describes the synthesis of the compound of Formula Ia, as its trifluoroacetic acid salt, as follows: 
In the above procedure, the pyrazole carboxylic acid and aniline are coupled and isolated as a free base. The 3-cyano-4-fluorophenyl group of the resulting product is then converted to 1-aminobenzisoxazole. One problem with this procedure is that the acid-aniline coupling product is difficult to purify. A second problem is that the conversion to the 1-aminobenzisoxazole moiety requires the presence of a strong, expensive base such as KOt-Bu.
It can be seen that the preparation of a compound of Formula I is difficult. Thus, it is desirable to find an efficient synthesis of such a compound.
Accordingly, one object of the present invention is to provide a novel process for preparing a compound of Formula I.
It is another object of the present invention to provide intermediates that are useful in preparing a compound of Formula I.
It is another object of the present invention to provide novel salt, crystalline, and solvent forms of Formula I.
It is another object of the present invention to provide pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt thereof.
It is another object of the present invention to provide a method for treating thromboembolic disorders comprising administering to a host in need of such treatment a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt thereof.
It is another object of the present invention to provide novel compounds for use in therapy.
It is another object of the present invention to provide the use of novel compounds for the manufacture of a medicament for the treatment of a thromboembolic disorder.
Thus, in an embodiment, the present invention provides a novel process for making a compound of Formula I: 
comprising:
(c) contacting a compound of Formula IVa with maleic acid to form a compound of Formula IV; 
(d) converting a compound of Formula IV to a compound of Formula V; and,
(e) forming a compound of Formula I.
In a preferred embodiment, in (c), contacting with maleic acid is performed in the presence of a first solvent, ethyl acetate.
In another preferred embodiment, in (c), a second solvent, 1-chlorobutane, is added to enhance precipitation.
In another preferred embodiment, (d) is performed by contacting a compound of Formula IV with HONHCOCH3 in the presence of a base and a solvent.
In another preferred embodiment, the base is selected from K2CO3, Na2CO3, KHCO3, NaHCO3, KF, NaOH, and KOH.
In another preferred embodiment, the base is K2CO3.
In another preferred embodiment, in (d), the solvent is selected from DMSO, DMAC, N-methylpyrrolidinone, and DMF.
In another preferred embodiment, in (d), the solvent is DMF, comprising: 0.5 to 50% by volume of water.
In another preferred embodiment, in (d), the solvent is DMF, comprising: 10, 11, 12, 13, 14, to 15% by volume of water.
In another preferred embodiment, in (d), the solvent is DMF, comprising: 15% by volume of water.
In another preferred embodiment, (e) is performed by contacting a compound of Formula V with HCl in a solvent selected from methanol, acetonitrile, isopropyl alcohol, ethanol, propanol, acetone, methyl isobutyl ketone (MIBK), 2-butanone, and water.
In another preferred embodiment, (e) is performed by contacting a compound of Formula V with HCl in ethanol.
In another preferred embodiment, the compound of Formula I is a mono-HCl salt.
In another preferred embodiment, the compound of Formula I is crystalline.
In another preferred embodiment, the compound of Formula I is a solvate selected from ethanol, propanol, isopropanol, acetone, MIBK, 2-butanone, and water.
In a more preferred embodiment, the compound of Formula I is an ethanol solvate.
In another embodiment, the present invention provides a novel process for making a compound of Formula IVa: 
comprising:
(b) coupling compounds of Formulas II and III to form a compound of Formula IVa.
In another preferred embodiment, the compound of Formula IVa is used without purification in (c).
In another preferred embodiment, (b) is performed by contacting a compound of Formula II with an acid activator, in a solvent and a first base, followed by contacting the resulting solution with a compound of Formula III.
In another preferred embodiment, (b) is performed by contacting a compound of Formula II with oxalyl chloride in acetonitrile and pyridine, followed by contacting the resulting solution with a compound of Formula III.
In another preferred embodiment, after a compound of Formula II has been contacted with a compound of Formula III, a second base is added to the reaction solution.
In another preferred embodiment, the second base is diisopropylethylamine.
In another embodiment, the present invention provides a novel process for making a compound of Formula II: 
comprising:
(a) contacting a compound of Formula VI with a compound of Formula VII to form a compound of Formula VIII; and,
(a1) converting a compound of Formula VIII to a compound of Formula II.
In another embodiment, the present invention provides a novel compound of Formula I: 
wherein I is a mono-HCl salt.
In another preferred embodiment, the compound of Formula I is crystalline.
In another preferred embodiment, the compound of Formula I is an ethanol solvate.
In another embodiment, the present invention provides a novel compound of Formula IV: 
In another embodiment, the present invention provides a novel compound of Formula Va: 
or a pharmaceutically acceptable salt form thereof.
In another embodiment, the present invention provides novel pharmaceutical compositions, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt form thereof.
In another embodiment, the present invention provides a novel method for treating a thromboembolic disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt form thereof.
In another embodiment, the present invention provides a compound of the present invention for use in therapy.
In another embodiment, the present invention provides the use of a compound of the present invention for the manufacture of a medicament for the treatment of a thromboembolic disorder.
As used herein, the following terms and expressions have the indicated meanings. It will be appreciated that the compounds of the present invention may contain an asymmetrically substituted carbon atom, and may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis from optically active starting materials. All chiral, diastereomeric, and racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomer form is specifically indicated.
The processes of the present invention are contemplated to be practiced on at least a multigram scale, kilogram scale, multikilogram scale, or industrial scale. Multigram scale, as used herein, is preferably the scale wherein at least one starting material is present in 10 grams or more, more preferably at least 50 grams or more, even more preferably at least 100 grams or more. Multikilogram scale, as used herein, is intended to mean the scale wherein more than one kilogram of at least one starting material is used. Industrial scale as used herein is intended to mean a scale which is other than a laboratory scale and which is sufficient to supply product sufficient for either clinical tests or distribution to consumers.
The term xe2x80x9csubstituted,xe2x80x9d as used herein, means that any one or more hydrogens on the designated atom are replaced with a selection from the indicated group, provided that the designated atom""s normal valency is not exceeded, and that the substitution results in a stable compound. When a substituent is keto (i.e., xe2x95x90O), then 2 hydrogens on the atom are replaced. Keto substituents are not present on aromatic moieties. When a ring system (e.g., carbocyclic or heterocyclic) is said to be substituted with a carbonyl group or a double bond, it is intended that the carbonyl group or double bond be part (i.e., within) of the ring.
The present invention is intended to include all isotopes of atoms occurring in the present compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium. Isotopes of carbon include C-13 and C-14.
The reactions of the synthetic methods claimed herein may be preferably carried out in the presence of a base, the base being any of a variety of bases, the presence of which in the reaction facilitates the synthesis of the desired product. Suitable bases may be selected by one of skill in the art of organic synthesis. Suitable bases include, but are not limited to, inorganic bases including, but not limited to, alkali metal, alkali earth metal, thallium, and ammonium hydroxides, alkoxides, phosphates, and carbonates, including, but not limited to, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, thallium hydroxide, thallium carbonate, tetra-n-butylammonium carbonate, and ammonium hydroxide.
The reactions of the synthetic methods claimed herein may be carried out in solvents that may be readily selected by one of skill in the art of organic synthesis, the solvents generally are any one that is substantially non-reactive with the starting materials (reactants), intermediates, or products at the temperatures at which the reactions are carried out, i.e., temperatures which may range from the solvent""s freezing temperature to the solvent""s boiling temperature. A given reaction may be carried out in one solvent or a mixture of more than one solvent. Depending on the particular reaction step, suitable solvents for a particular reaction step may be selected.
Suitable ether solvents include: dimethoxymethane, tetrahydrofuran, 1,3-dioxane, 1,4-dioxane, furan, diethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, triethylene glycol dimethyl ether, or t-butyl methyl ether.
Suitable aprotic solvents may include, by way of example and without limitation, tetrahydrofuran (THF), dimethylformamide (DMF), dimethylacetamide (DMAC), 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU), 1,3-dimethyl-2-imidazolidinone (DMI), N-methylpyrrolidinone (NMP), formamide, N-methylacetamide, N-methylformamide, acetonitrile, dimethyl sulfoxide, propionitrile, ethyl formate, methyl acetate, hexachloroacetone, acetone, ethyl methyl ketone, ethyl acetate, sulfolane, N,N-dimethylpropionamide, tetramethylurea, nitromethane, nitrobenzene, or hexamethylphosphoramide.
The phrase xe2x80x9cpharmaceutically acceptablexe2x80x9d is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
As used herein, xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic groups including, but not limited to, amines, and alkali or organic salts of acidic groups including, but not limited to, carboxylic acids. The pharmaceutically acceptable salts include conventional non-toxic salts or quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, conventional non-toxic salts include those derived from inorganic acids including, but not limited to, hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, and nitric; and the salts prepared from organic acids including, but not limited to, acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, and isethionic.
The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound that contains a basic or acidic moiety by conventional chemical methods. Generally, salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile is preferred. Lists of suitable salts are found in Remington""s Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, the disclosure of which is hereby incorporated by reference.
As used herein, xe2x80x9ctreatingxe2x80x9d or xe2x80x9ctreatmentxe2x80x9d cover the treatment of a disease-state in a mammal, particularly in a human, and include: (a) preventing the disease-state from occurring in a mammal, in particular, when such mammal is predisposed to the disease-state but has not yet been diagnosed as having it; (b) inhibiting the disease-state, i.e., arresting it development; and/or (c) relieving the disease-state, i.e., causing regression of the disease state.
The processes of the present invention can be practiced in a number of ways depending on the solvent, base, and temperature chosen. As one of ordinary skill in the art of organic synthesis recognizes, the time for reaction to run to completion as well as yield will be dependent upon all of the variables selected. The following schemes show a representation of the overall sequence of the present invention.
Preparation of Formula VIII: 
VI can be converted to VIII by a novel hydrazine in situ trapping procedure. The hydrazine intermediate can be prepared by treating VI with HCl and NaNO2. Preferably, VI is added to a cooled (e.g., xe2x88x9210 to xe2x88x925xc2x0 C.) solution of HCl. The NaNO2 can then added and the solution preferably maintained at a temperature of from 0-10xc2x0 C. At this point, AcOH can be added to the solution. SnCl2.2H2O can then be added to complete formation of the hydrazine. The resulting product may be isolated or used in situ. Preferably, it is used in situ.
VIII can then be formed by addition of VII to the newly formed hydrazine. This addition is preferably performed in the presence of MeOH and at a temperature of from 35-55xc2x0 C.
Preparation of Formula II: 
Oxidation of VIII should provide II. The oxidation is performed by contacting VIII with an oxidant in the presence of a solvent and optionally a buffer.
One of ordinary skill in the art would recognize that oxidants such as KMnO4 or NaClO2 can be used. Preferably, KMnO4, in the presence of a buffer, is used as the oxidant. VIII can be suspended in an alcoholic solvent (e.g., t-butyl alcohol). The suspension is preferably maintained at a temperature of from 35-50xc2x0 C. An aqueous solution of a buffer known to those of skill in the art (e.g., monobasic sodium phosphate monohydrate) can then be added. Preferably, the buffer is about 0.5 to 4N. Aqueous KMnO4 can then be added to the reaction solution. After the reaction is complete, II can be isolated.
Preparation of Formula IVa: 
IVa can be formed by coupling II and III. The coupling is preferably performed by contacting II with an acid activator, in a solvent and in the presence of a base, followed by contacting the resulting solution with III. An acid activator like thionyl chloride or oxalyl chloride can be used, with oxalyl chloride being a preferred activator. The addition of the acid activator is preferably performed at a temperature of from 10-30xc2x0 C.
Contacting II and oxalyl chloride can be performed in a solvent selected from acetonitrile, THF, and methylene chloride, with acetonitrile being preferred. The first base can be selected from DMAP, triethylamine, diisopropylethylamine, N-methyl morpholine, and pyridine, with pyridine being preferred. The amount of first base present is preferably from 0.2 to 1 molar equivalent based on II, more preferably it is 0.4 molar equivalents.
The desired amount of oxalyl chloride to be added will be based on the amount of II present in the solution and the amount of water present in the solution. The amount of water present can be determined by known means, such as the Karl Fischer titration. Preferably, the number of moles of oxalyl chloride added is equal to or slightly greater than the sum of the number of moles of II and water present.
Once II has been activated, it can be contacted with III. Preferably, the reaction mixture is cooled to from 0-10xc2x0 C. prior to contacting with III. After contacting III with the reaction mixture, a second base is preferably added. The second base can be selected from diisopropylethylamine, pyridine, DMAP, triethylamine, and N-methyl morpholine, with diisopropylethylamine being preferrred. The amount of second base present is preferably from about 1-3 molar equivalents, more preferably about 2.2 molar equivalents based on the amount of II present.
Preparation of Formula IV: 
IV can be formed from IVa with or without purification of IVa. Preferably, IV is formed from IVa without purification. IVa is usually isolated as an oily substance. IVa is preferably taken up in a first solvent and maleic acid is added. To this solution can be added a second solvent to enhance or accelerate precipitation of IV. Preferably from 0.9 to 1.1 molar equivalents of maleic acid are present based on the amount of II present, more preferably about 0.95 molar equivalents. The first solvent can be selected from the group acetone, chloroform, ethyl acetate MIBK, i-propyl acetate, i-propyl alcohol, and THF, and is preferably ethyl acetate. The second solvent can be selected from the group 1-chlorobutane, heptane, hexane, methylene chloride, and TBME, and is preferably 1-chlorobutane. Preferably, this reaction is run at about room temperature.
Preparation of Formula V: 
V can be prepared by contacting IV with HONHCOCH3 in the presence of a base and a solvent. Preferably, the base is selected from K2CO3, Na2CO3, KHCO3, NaHCO3, KF, NaOH, and KOH, with K2CO3 being a more preferred base. The solvent may be selected from DMSO, dimethylformamide (DMF), dimethylacetamide (DMAC), 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU), 1,3-dimethyl-2-imidazolidinone (DMI), and N-methylpyrrolidinone (NMP). A preferred solvent is DMF. It is preferred that the DMF comprises 0.5 to 50% by volume of water, more preferably, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, to 15% by volume of water, even more preferably 10, 11, 12, 13, 14, to 15% by volume of water, and still more preferably 15% by volume of water.
Preferably, HONHCOCH3, DMF, and K2CO3 are mixed together followed by contacting with water. This reaction mixture is preferably kept at about 20-30xc2x0 C. Upon contacting of the reaction mixture with IV, the reaction is preferably stirred at about room temperature.
Preparation of Formula I: 
I can be formed from V by dissolving V in a solvent and contacting this solution with HCl. Preferably, the solvent is selected from methanol, acetonitrile, isopropyl alcohol, ethanol, propanol, acetone, methyl isobutyl ketone (MIBK), 2-butanone, and water, with ethanol being a more preferred solvent. V is preferably taken up in a solvent (e.g., ethanol) at a temperature of from 60-80xc2x0 C. HCl is preferably contacted with the solution that is at a temperature of from 20-40xc2x0 C. Preferably, the HCl is in an alcoholic solution. The alcoholic solution is preferably i-propyl alcohol.
I preferably precipitates from the reaction mixture. This precipitation can be enhanced by cooling the mixture to a temperature of about 0-10xc2x0 C. Preferably I is a crystalline mono-HCl salt. More preferably, I is a solvate selected from ethanol, propanol, isopropanol, acetone, MIBK, 2-butanone, and water. Even more preferably, I is an ethanol solvate.
Other features of the invention will become apparent in the course of the following descriptions of exemplary embodiments that are given for illustration of the invention and are not intended to be limiting thereof.